Aurora A is a serine/threonine kinase. It is reported that Aurora A is involved in e.g., formation and maturation of a centrosome, spindle kinetics and chromosome alignment in the mitotic phase (M phase) of the cell cycle and regulates a process of mitotic division (Non Patent Document 1). Up to present, it has been confirmed that Aurora A is excessively expressed and/or amplified in a wide variety of types of carcinomas (Non Patent Document 2). Furthermore, inhibition of Aurora A kinase in a tumor cell induces arrest of mitotic division and induction of apoptosis. Thus, Aurora A is an important target molecule for cancer treatment.
Microtubule-targeting drugs such as taxane antitumor agents and vinca alkaloids have been widely used as cancer chemotherapeutic agents. However, due to refractoriness and resistance to these agents, sufficient therapeutic effects are not sometimes obtained. Thus, it is expected that an agent capable of enhancing the antitumor effect of a taxane antitumor agent can more effectively treat cancer. In the cytotoxicity reaction of a taxane antitumor agent, it is required to activate a spindle assembly checkpoint in a cell cycle. In tumor cells reduced in this activity, sensitivity to a taxane antitumor agent decreases (Non Patent Document 3), in addition, a cell strain, in which Aurora A is excessively expressed, develops resistance to paclitaxel (Non Patent Document 4). Thus, it has been reported that an effect of paclitaxel or docetaxel is enhanced if Aurora A is inhibited (Non Patent Document 5).
In the meantime, Aurora B, which is a subtype of Aurora A, acts on the mitotic phase (M phase) of the cell cycle similarly to Aurora A. However, it has been reported that if Aurora B is inhibited, the activity of a spindle checkpoint is reduced (Non Patent Document 6). Thus, there is a possibility that inhibition of Aurora B may attenuate the effect of a taxane antitumor agent. From the descriptions above, it is expected that if an agent selectively inhibiting Aurora A kinase is used in combination with a taxane antitumor agent, its antitumor effect can be enhanced to produce a higher therapeutic effect.
Under the above circumstance, MK-5108 is reported as an Aurora A selective inhibitor (Non Patent Document 7). In this document, an antitumor effect is evaluated by administering MK-5108 and docetaxel to nude rats. To describe it more specifically, docetaxel is administered and then, 24 hours later, MK-5108 is orally administered twice per day over 2 days. Although enhancement of an antitumor effect is confirmed, its therapeutic effect is not sufficient.